CRITICAL ROLE OF PHOSPHAGENS IN THE ENERGY CASCADE OF CUTANEOUS ISCHEMIA AND PROTECTIVE ACTION OF PHOSPHOCREATINE ANALOGS IN SKIN FLAP SURVIVAL

A general understanding of the pivotal role of phosphocreatine (PCr) a s the principal determinant of skin flap survival is now emerging. Def initive metabolic investigations using phosphorus (P-31) and proton (H -1) magnetic resonance spectroscopy (MRS) have established that the in ability to replenish metabolically exhausted PCr reserves predictably correlates with skin flap necrosis. Furthermore, postoperative parente ral administration of PCr has been shown to augment effectively skill flap survival. We hypothesized that creatine kinase, the enzyme contro lling the utilization of the high-energy phosphate component of PCr, i s a critical determinant of the tolerance of a skin flap to ischemic i nsult. In other words, if the rate of utilization of PCr is too rapid, PCr stores will rapidly deplete, and the flap will not be able to wit hstand a period of ischemia. Alternatively, if the late of dephosphory lation of PCr is reduced, survival of skin flaps during periods of isc hemia could be extended. To test this hypothesis, we investigated the metabolic distribution and fate of cyclo-creatine (cCr), a competent c reatine analogue with a lower affinity for the creatine kinase enzyme. When administered as 1.5 percent (w/w) of the normal diet of laborato ry rats, cCr accumulates in skin as the competent phosphagen, phosphoc yclocreatine (PcCr). Cutaneous flaps elevated in these animals, and st udied by P-31 and H-1 MRS, demonstrate that once depletion of PCr has occurred, PcCr continues to sustain ATP levels. This results in signif icant enhancement of skill flap survival (p < 0.005). These observatio ns confirm the importance of the creatine kinase enzyme in cutaneous f lap ischemia and suggest new approaches to augment skin flap survival.